Clardy J
Department of Chemistry, Cornell University, Ithaca, NY 14853-1301.
Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):56-61. doi: 10.1073/pnas.92.1.56.
Several disciplines, including chemical ecology, seek to understand the molecular basis of information transfer in biological systems, and general molecular strategies are beginning to emerge. Often these strategies are discovered by a careful analysis of natural products and their biological effects. Cyclosporin A, FK506, and rapamycin are produced by soil microorganisms and are being used or considered as clinical immunosuppressive agents. They interrupt the cytoplasmic portion of T-cell signaling by forming a complex with a binding protein--FKBP12 in the case of FK506 and rapamycin and cyclophilin A (CyPA) in the case of cyclosporin A (CsA). This complex in turn inhibits a protein target, and the best understood target is calcineurin, which is inhibited by FK506-FKBP12 and CyPA-CsA. Mutational and structural studies help define how FK506-FKBP12 interacts with calcineurin, and the results of these studies are summarized. The existence of strong FK506-FKBP12 binding suggests that FK506 is mimicking some natural ligand for FKBP12. Synthetic and structural studies to probe this mimicry are also described.
包括化学生态学在内的多个学科都致力于理解生物系统中信息传递的分子基础，一些通用的分子策略也开始显现出来。这些策略通常是通过对天然产物及其生物学效应进行细致分析而发现的。环孢菌素A、FK506和雷帕霉素由土壤微生物产生，目前正在作为临床免疫抑制剂使用或被考虑用于临床。它们通过与一种结合蛋白形成复合物来干扰T细胞信号传导的细胞质部分——FK506和雷帕霉素的情况下是与FKBP12结合，环孢菌素A（CsA）的情况下是与亲环蛋白A（CyPA）结合。这种复合物进而抑制一种蛋白质靶点，目前了解得最清楚的靶点是钙调神经磷酸酶，它会被FK506 - FKBP12和CyPA - CsA抑制。突变和结构研究有助于确定FK506 - FKBP12与钙调神经磷酸酶是如何相互作用的，本文总结了这些研究的结果。FK506与FKBP12之间存在强结合，这表明FK506正在模拟FKBP12的某种天然配体。本文还描述了用于探究这种模拟作用的合成和结构研究。
